Efficacy and Safety Study of PCI-32765 Combine With Ofatumumab in CLL (PCYC-1109-CA)

An Open-label, Phase 1b/2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, and Ofatumumab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Prolymphocytic Leukemia

The purpose of this study is to determine the efficacy and safety of a fixed-dose, daily regimen of orally administered PCI-32765 combined with ofatumumab in subjects with relapsed/refractory CLL/SLL and related diseases

Study Overview

• Status: Completed
• Conditions: B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Richter's Transformation; Prolymphocyctic Leukemia
• Intervention / Treatment: Drug: PCI-32765; Drug: ofatumumab

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects with histologically confirmed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or Richter's transformation arising out of CLL/SLL as defined by WHO classification of hematopoietic neoplasms and satisfying ≥ 1 of the following conditions:

   • Progressive splenomegaly and/or lymphadenopathy identified by physical examination or radiographic studies
   • Anemia (<11 g/dL) or thrombocytopenia (<100,000/μL) due to bone marrow involvement
   • Presence of unintentional weight loss > 10% over the preceding 6 months
   • NCI CTCAE Grade 2 or 3 fatigue
   • Fevers > 100.5 degree or night sweats for > 2 weeks without evidence of infection
   • Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of < 6 months
   • Need for cytoreduction prior to stem cell transplant
2. Subjects must have failed ≥ 2 prior therapies for CLL including a nucleoside analog or ≥ 2 prior therapies not including nucleoside analog if there is a contraindication to such therapy
3. 10% expression of CD20 on CLL/SLL cells
4. ECOG performance status ≤ 2
5. Life expectancy ≥ 12 weeks

6. Subjects must have organ and marrow function as defined below:

   • Absolute neutrophil count (ANC) ≥ 1000/µL in the absence of bone marrow involvement
   • Platelets ≥ 30,000/μL in the absence of bone marrow involvement
   • Total bilirubin ≤ 1.5 x institutional upper limit of normal unless due to Gilbert's disease
   • AST (SGOT) ≤ 2.5 x institutional upper limit of normal unless due to infiltration of the liver
   • Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min
7. No history of prior exposure to ofatumumab
8. Age ≥ 18 years
9. Body weight ≥ 40 kg

Exclusion Criteria:

1. A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk
2. Significant cardiovascular disease
3. Any condition which could interfere with the absorption or metabolism of PCI-32765 including unable to swallow capsules, malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
4. Known history of Human Immunodeficiency Virus (HIV) or active infection with Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) or any uncontrolled active systemic infection
5. Any anticancer immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 4 weeks before first dose of study drug. Corticosteroids for disease-related symptoms are allowed provided 1 week washout occurs
6. Active central nervous system (CNS) involvement by lymphoma
7. Major surgery within 4 weeks before first dose of study drug
8. Lactating or pregnant
9. Known moderate to severe chronic obstructive pulmonary disease (COPD)
10. History of prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for at least 2 years or which will not limit survival to < 2 years
11. History of Grade ≥ 2 toxicity continuing from prior anticancer therapy including radiation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; In Group 1, PCI-32765 420 mg PO was administered daily for 1 cycle (28 days) before the start of ofatumumab IV dosing	Drug: PCI-32765; 420 mg PO daily; Other Names: ibrutinib; Drug: ofatumumab; per package insert as an IV infusion; Other Names: Arzerra
Experimental: Group 2; In Group 2, PCI-32765 420 mg PO daily was initiated concomitantly with ofatumumab IV (PCI-32765 initiated on Day 2 of Cycle 1)	Drug: PCI-32765; 420 mg PO daily; Other Names: ibrutinib; Drug: ofatumumab; per package insert as an IV infusion; Other Names: Arzerra
Experimental: Group 3; In Group 3, two cycles of ofatumumab IV were administered prior to the start of PCI-32765 420 mg PO daily	Drug: PCI-32765; 420 mg PO daily; Other Names: ibrutinib; Drug: ofatumumab; per package insert as an IV infusion; Other Names: Arzerra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Response	The primary endpoint for the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR), CR with incomplete blood count recovery (Cri), or partial response (PR), according to the guidelines from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL1) published in 2008 for CLL participants and International Working Group for non-Hodgkin's lymphoma (IWG NHL) 2007 criteria for SLL participants, with the modification that treatment-related lymphocytosis will not be considered progressive disease, as evaluated by the investigators. Assessment of disease is based on radiological exams, physical exam, hematological evaluations and, when appropriate, bone marrow results.	The median follow-up time on study for all treated participants is 12.5 (range 0.5-19.6) months
Safety During Dose-Limiting Toxicity (DLT) Observation Period	Number of dose-limiting toxicities observed in the first 6 participants enrolled in treatment Groups 1 and 2	56 days for Group 1 and 28 days for Group 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (AEs)	Number of participants who had experienced at least one treatment emergent AE	From first dose of study treatment to within 30 days of last dose or until study closure
Progression Free Survival (PFS) at 12 Months	Progressive disease for CLL (Hallek) is characterized by ≥1 of the following: Appearance of any new lesion, eg lymph nodes (> 1.5 cm), de novo hepatomegaly or splenomegaly, or other organ infiltrates; Increase of ≥50%in longest diameter of any previous sitein hepatomegaly or splenomegalyin blood lymphocytes with ≥5x109/L B cells with enlarging lymph node, liver, or spleen Progressive disease for B cell lymphoma (Cheson) is characterized by any new lesion or increase by ≥ 50% of previously involved sites from nadir: Appearance of a new lesion(s) >1.5 cm in any axis, ≥ 50% increase in the SPD of >1 node, or ≥50% increase in longest diameter of a previously identified node >1 cm in short axis; Lesions PET+ if FDG-avid lymphoma or PET+ before therapy; 50% increase from nadir in the SPD of any liver or spleen lesions; New or recurrent BM involvement; Increase of ≥50% in blood lymphocytes with ≥5x109/L B cells within enlarging lymph node, liver, or spleen	From first dose of study treatment until disease progression, death, or until 12 months

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.
• Collaborators: Ohio State University
• Investigators: Principal Investigator: Samantha Jaglowski, MD, Ohio State University

Publications and helpful links

General Publications

• Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, Lacey SF, Melenhorst JJ, McGettigan SE, Cook DR, Zhang C, Xu J, Do P, Hulitt J, Kudchodkar SB, Cogdill AP, Gill S, Porter DL, Woyach JA, Long M, Johnson AJ, Maddocks K, Muthusamy N, Levine BL, June CH, Byrd JC, Maus MV. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016 Mar 3;127(9):1117-27. doi: 10.1182/blood-2015-11-679134. Epub 2016 Jan 26.
• Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Lozanski A, Davis M, Gordon A, Smith LL, Mantel R, Jones JA, Flynn JM, Jaglowski SM, Andritsos LA, Awan F, Blum KA, Grever MR, Johnson AJ, Byrd JC, Woyach JA. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015 Apr;1(1):80-7. doi: 10.1001/jamaoncol.2014.218.
• Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, Maddocks KJ, Woyach JA, Blum KA, Grever MR, Smucker K, Ruppert AS, Heerema NA, Lozanski G, Stefanos M, Munneke B, West JS, Neuenburg JK, James DF, Hall N, Johnson AJ, Byrd JC. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015 Aug 13;126(7):842-50. doi: 10.1182/blood-2014-12-617522. Epub 2015 Jun 26.
• Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, Hessler JD, Liu TM, Chang BY, Larkin KM, Stefanovski MR, Chappell DL, Frissora FW, Smith LL, Smucker KA, Flynn JM, Jones JA, Andritsos LA, Maddocks K, Lehman AM, Furman R, Sharman J, Mishra A, Caligiuri MA, Satoskar AR, Buggy JJ, Muthusamy N, Johnson AJ, Byrd JC. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013 Oct 10;122(15):2539-49. doi: 10.1182/blood-2013-06-507947. Epub 2013 Jul 25.

Helpful Links

• www.pharmacyclics.com

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: October 7, 2010
• First Submitted That Met QC Criteria: October 7, 2010
• First Posted (Estimate): October 8, 2010

Study Record Updates

• Last Update Posted (Estimate): June 25, 2015
• Last Update Submitted That Met QC Criteria: May 28, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Antineoplastic Agents; Ofatumumab
• Other Study ID Numbers: PCYC-1109-CA; PCI-32765 (Other Identifier: Pharmacyclics)